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Alterations in BNST Intrinsic Functional Connectivity in Early Abstinence from Alcohol Use Disorder.Alcohol and Alcoholism (Oxford,... May 2023Maintaining abstinence from alcohol use disorder (AUD) is extremely challenging, partially due to increased symptoms of anxiety and stress that trigger relapse. Rodent...
AIMS
Maintaining abstinence from alcohol use disorder (AUD) is extremely challenging, partially due to increased symptoms of anxiety and stress that trigger relapse. Rodent models of AUD have identified that the bed nucleus of the stria terminalis (BNST) contributes to symptoms of anxiety-like behavior and drug-seeking during abstinence. In humans, however, the BNST's role in abstinence remains poorly understood. The aims of this study were to assess BNST network intrinsic functional connectivity in individuals during abstinence from AUD compared to healthy controls and examine associations between BNST intrinsic functional connectivity, anxiety and alcohol use severity during abstinence.
METHODS
The study included resting state fMRI scans from participants aged 21-40 years: 20 participants with AUD in abstinence and 20 healthy controls. Analyses were restricted to five pre-selected brain regions with known BNST structural connections. Linear mixed models were used to test for group differences, with sex as a fixed factor given previously shown sex differences.
RESULTS
BNST-hypothalamus intrinsic connectivity was lower in the abstinent group relative to the control group. There were also pronounced sex differences in both the group and individual analyses; many of the findings were specific to men. Within the abstinent group, anxiety was positively associated with BNST-amygdala and BNST-hypothalamus connectivity, and men, not women, showed a negative relationship between alcohol use severity and BNST-hypothalamus connectivity.
CONCLUSIONS
Understanding differences in connectivity during abstinence may help explain the clinically observed anxiety and depression symptoms during abstinence and may inform the development of individualized treatments.
Topics: Humans; Male; Female; Alcoholism; Septal Nuclei; Anxiety; Magnetic Resonance Imaging; Amygdala
PubMed: 36847484
DOI: 10.1093/alcalc/agad006 -
British Journal of Anaesthesia May 2023Sepsis-associated encephalopathy is characterised by cognitive dysfunction, and might be mediated by deficits in neurotransmission. Reduced cholinergic neurotransmission...
BACKGROUND
Sepsis-associated encephalopathy is characterised by cognitive dysfunction, and might be mediated by deficits in neurotransmission. Reduced cholinergic neurotransmission in the hippocampus impairs memory function. We assessed real-time alterations of acetylcholine neurotransmission from the medial septal nucleus to the hippocampus, and explored whether sepsis-induced cognitive deficits can be relieved by activating upstream cholinergic projections.
METHOD
Lipopolysaccharide (LPS) injection or caecal ligation and puncture (CLP) was used to induce sepsis and associated neuroinflammation in wild-type and mutant mice. Adeno-associated viruses for calcium and acetylcholine imaging, and for optogenetic and chemogenetic modulation of cholinergic neurones were injected into the hippocampus or medial septum, and a 200-μm-diameter optical fibre was implanted to collect acetylcholine and calcium signals. Cholinergic activity of the medial septum was manipulated and combined with cognitive assessment after LPS injection or CLP.
RESULTS
Intracerebroventricular LPS injection reduced postsynaptic acetylcholine (from 0.146 [0.001] to 0.0047 [0.0005]; p=0.004) and calcium (from 0.0236 [0.0075] to 0.0054 [0.0026]; p=0.0388) signals in hippocampal Vglut2-positive glutamatergic neurones, whereas optogenetic activation of cholinergic neurones in the medial septum reversed LPS-induced reductions in these two signals. Intraperitoneal LPS injection decreased acetylcholine concentration in the hippocampus (476 [20] pg ml to 382 [14] pg ml; p=0.0001). Reduction in long-term potentiation (238 [23] % to 150 [12] %; p=0.0082) and enhancement of hippocampal pyramidal neurone action potential frequency (5.8 [1.5] Hz to 8.2 [1.8] Hz; p=0.0343) were relieved, and neurocognitive performance was improved by chemogenetic activation of cholinergic innervation of the hippocampus 3 days after LPS injection in septic mice.
CONCLUSIONS
Systemic or local LPS reduced cholinergic neurotransmission from the medial septum to hippocampal pyramidal neurones, and their selective activation alleviated defects in hippocampal neuronal function and synaptic plasticity and ameliorated memory deficits in sepsis model mice through enhanced cholinergic neurotransmission. This provides a basis for targeting cholinergic signalling to the hippocampus in sepsis-induced encephalopathy.
Topics: Mice; Animals; Septal Nuclei; Acetylcholine; Lipopolysaccharides; Calcium; Hippocampus; Synaptic Transmission; Cognitive Dysfunction; Sepsis; Cognition; Cholinergic Agents
PubMed: 36813621
DOI: 10.1016/j.bja.2023.01.019 -
Neuropharmacology May 2023Defensive behaviors in response to a threat are shared across the animal kingdom. Active (fleeing, sheltering) or passive (freezing, avoiding) defensive responses are... (Review)
Review
Defensive behaviors in response to a threat are shared across the animal kingdom. Active (fleeing, sheltering) or passive (freezing, avoiding) defensive responses are adaptive and facilitate survival. Selecting appropriate defensive strategy depends on intensity, proximity, temporal threat threshold, and past experiences. Hypothalamic corticotropin-releasing factor (CRF) is a major driver of an acute stress response, whereas extrahypothalamic CRF mediates stress-related affective behaviors. In this review, we shift the focus from a monolithic role of CRF as an anxiogenic peptide to comprehensively dissecting contributions of distinct populations of CRF neurons in mediating defensive behaviors. Direct interrogation of CRF neurons of the central amygdala (CeA) or the bed nucleus of the stria terminalis (BNST) show they drive unconditioned defensive responses, such as vigilance and avoidance of open spaces. Although both populations also contribute to learned fear responses in familiar, threatening contexts, CeA-CRF neurons are particularly attuned to the ever-changing environment. Depending on threat intensities, they facilitate discrimination of salient stimuli predicting manageable threats, and prevent their generalization. Finally, hypothalamic CRF neurons mediate initial threat assessment and active defense such as escape to shelter. Overall, these three major populations of CRF neurons demonstrate divergent, yet complementary contributions to the versatile defense system: heightened vigilance, discriminating salient threats, and active escape, representing three legs of the defense tripod. Despite the 'CRF exhaustion' in the field of affective neuroscience, understanding contributions of specific CRF neurons during adaptive defensive behaviors is needed in order to understand the implications of their dysregulation in fear- and anxiety-related psychiatric disorders. This article is part of the Special Issue on "Fear, Anxiety and PTSD".
Topics: Animals; Corticotropin-Releasing Hormone; Fear; Neurons; Anxiety; Central Amygdaloid Nucleus; Adrenocorticotropic Hormone; Septal Nuclei
PubMed: 36775096
DOI: 10.1016/j.neuropharm.2023.109461 -
Frontiers in Neural Circuits 2022
Topics: Septal Nuclei; Hippocampus
PubMed: 36712837
DOI: 10.3389/fncir.2022.1093711 -
Frontiers in Neural Circuits 2022The bed nucleus of the stria terminalis (BNST) is a highly heterogeneous limbic forebrain structure that serves as a relay connecting autonomic, neuroendocrine and...
The bed nucleus of the stria terminalis (BNST) is a highly heterogeneous limbic forebrain structure that serves as a relay connecting autonomic, neuroendocrine and behavioral function. It can be divided into over 16 individual subregions with distinct neuronal subpopulations based on receptors, transmitters, and neuropeptides. Specifically, the BNST projection to the ventral tegmental area (VTA), the dopamine hub of the brain, has been shown to have a crucial role in the stress response. However, in mice there is a lack of unbiased data on the functional diversity of this sub-population which serves as an upstream input to the VTA. The dopaminergic neurons in the VTA modify their ion channel activity and intrinsic membrane properties to adapt to stress in part from inputs from BNST projections. Therefore, we aimed to perform a multi-component characterization of the functional diversity of the BNST-VTA pathway. We studied the passive and active electrophysiological properties of virally identified population of BNST neurons that project to the VTA. We used a comprehensive series of recordings of electrophysiological variables and performed hierarchical clustering to determine the functional diversity of the projection neurons in the BNST-VTA pathway. Our study revealed four subpopulations in the BNST-VTA pathway, all of which differ in their activation profiles and likely have distinct inputs and function in the VTA. Our results will help resolve the discord in interpretation of the various roles of this electrophysiologically diverse projection and builds a foundation for understanding how the different neuronal types integrate signals.
Topics: Mice; Animals; Ventral Tegmental Area; Septal Nuclei; Dopaminergic Neurons; Dopamine; Interneurons
PubMed: 36698552
DOI: 10.3389/fncir.2022.1081099 -
Neuroscience and Biobehavioral Reviews Mar 2023We suggest that to understand complex behaviors associated with fear and anxiety, we need to understand brain processes at the collective, network level. But what should... (Review)
Review
We suggest that to understand complex behaviors associated with fear and anxiety, we need to understand brain processes at the collective, network level. But what should be the type and spatial scale of the targeted circuits/networks? Not only are multi-region interactions essential-including complex reciprocal interactions, loops, and other types of arrangement-but it is profitable to characterize circuits spanning the entire neuroaxis. In particular, it is productive to conceptualize the circuits contributing to fear/anxiety as embedded into large-scale connectional systems. We discuss circuits involving the basolateral amygdala that contribute to aversive conditioning and fear extinction. In addition, we highlight the importance of the extended amygdala (central nucleus of the amygdala and bed nucleus of the stria terminalis) cortical-subcortical loop, which allows large swaths of cortex and subcortex to influence fear and anxiety. In this manner, fear/anxiety can be understood not only based on traditional "descending" mechanisms involving the hypothalamus and brainstem, but in terms of a considerably broader reentrant organization.
Topics: Humans; Fear; Extinction, Psychological; Anxiety; Brain; Anxiety Disorders; Septal Nuclei
PubMed: 36634832
DOI: 10.1016/j.neubiorev.2023.105039 -
Journal of Morphology Feb 2023Androgens and their receptors are present throughout the body. Various structures such as muscles, genitals, and prostate express androgen receptors. The central nervous...
Androgens and their receptors are present throughout the body. Various structures such as muscles, genitals, and prostate express androgen receptors. The central nervous system also expresses androgen receptors. Androgens cross the blood-brain barrier to reach these central areas. In the central nervous system, androgens are involved in multiple functions. The current study investigated in which forebrain areas androgens are expressed in the male cat. Androgen receptor immunoreactive (AR-IR) nuclei were plotted and the results were quantified with a Heidelberg Topaz II + scanner and Linocolor 5.0 software. The density and intensity of the labeled cells were the main outcomes of interest. The analysis revealed a dense distribution of AR-IR nuclei in the preoptic area, periventricular complex of the hypothalamus, posterior hypothalamic area, ventromedial hypothalamic, parvocellular hypothalamic, infundibular, and supramammillary nucleus. Numerous AR-IR cells were also observed in the dorsal division of the anterior olfactory nucleus, lateral septal nucleus, medial and lateral divisions of the bed nucleus of the stria terminalis, lateral olfactory tract nucleus, anterior amygdaloid area, and the central and medial amygdaloid nuclei. AR-IR nuclei were predominantly observed in areas involved in autonomic and neuroendocrinergic responses which are important for many physiological processes and behaviors.
Topics: Animals; Male; Androgens; Hypothalamus; Receptors, Androgen; Telencephalon; Cats
PubMed: 36601705
DOI: 10.1002/jmor.21553 -
Sleep and Biological Rhythms Apr 2023This study aimed to investigate the alterations in limbic structure volumes and limbic covariance network in patients with isolated rapid eye movement (REM) sleep...
This study aimed to investigate the alterations in limbic structure volumes and limbic covariance network in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD) and to compare them with healthy controls. We retrospectively enrolled 35 patients with iRBD and 35 healthy controls who underwent three-dimensional T1-weighted brain MRI. Volumetric analysis of subcortical limbic structures, including the hippocampus, amygdala, thalamus, mammillary body, hypothalamus, basal forebrain, septal nuclei, fornix, and nucleus accumbens, was performed. Furthermore, the limbic covariance network was examined using graph theory based on the limbic structure volumes. Some of the limbic structure volumes differed significantly. The right amygdala and hypothalamus volumes were lower in the patients with iRBD than in the healthy controls (0.101% vs. 0.114%, = 0.016, and 0.027% vs. 0.030%, = 0.045, respectively). However, there were no significant differences in the limbic covariance network between the groups. This study demonstrated that the volumes of the right amygdala and hypothalamus are lower in patients with iRBD, even without cognitive impairments, than in healthy controls. However, there were no significant differences in the limbic covariance network between the groups. The involvements of the limbic structures could be related to the conversion to neurodegenerative diseases in patients with iRBD.
PubMed: 38469290
DOI: 10.1007/s41105-022-00440-2 -
Neuropharmacology Mar 2023Nearly one percent of children in the US experience childhood neglect or abuse, which can incite lifelong emotional and behavioral disorders. Many studies investigating... (Review)
Review
Nearly one percent of children in the US experience childhood neglect or abuse, which can incite lifelong emotional and behavioral disorders. Many studies investigating the neural underpinnings of maleffects inflicted by early life stress have largely focused on dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Newer veins of evidence suggest that exposure to early life stressors can interrupt neural development in extrahypothalamic areas as well, including the bed nucleus of the stria terminalis (BNST). One widely used approach in this area is rodent maternal separation (MS), which typically consists of separating pups from the dam for extended periods of time, over several days during the first weeks of postnatal life - a time when pups are highly dependent on maternal care for survival. MS has been shown to incite myriad lasting effects not limited to increased anxiety-like behavior, hyper-responsiveness to stressors, and social behavior deficits. The behavioral effects of MS are widespread and thus unlikely to be limited to hypothalamic mechanisms. Recent work has highlighted the BNST as a critical arbiter of some of the consequences of MS, especially socioemotional behavioral deficits. The BNST is a well-documented modulator of anxiety, reward, and social behavior by way of its connections with hypothalamic and extra-hypothalamic systems. Moreover, during the postnatal period when MS is typically administered, the BNST undergoes critical neural developmental events. This review highlights evidence that MS interferes with neural development to permanently alter BNST circuitry, which may account for a variety of behavioral deficits seen following early life stress. This article is part of the Special Issue on 'Fear, Anxiety and PTSD'.
Topics: Humans; Septal Nuclei; Maternal Deprivation; Anxiety; Fear; Anxiety Disorders
PubMed: 36572178
DOI: 10.1016/j.neuropharm.2022.109404 -
Psychoneuroendocrinology Mar 2023BTBR T Itpr3/J (BTBR) mice display several behavioral characteristics, including social deficits resembling the core symptoms of human autism. Atypical social behaviors...
Faded neural projection from the posterior bed nucleus of the stria terminalis to the lateral habenula contributes to social signaling deficit in male BTBR mice as a mouse model of autism.
BTBR T Itpr3/J (BTBR) mice display several behavioral characteristics, including social deficits resembling the core symptoms of human autism. Atypical social behaviors include sequential processes of assembled cognitive-behavior components, such as recognition, investigatory assessment, and signaling response. This study aimed to elucidate the neural circuits responsible for the regulation of the social signaling response, as shown by scent marking behavior in male mice. We first assessed the recognition and investigatory patterns of male BTBR mice compared to those of C57BL/6 J (B6) mice. Next, we examined their scent-marking behavior as innate social signaling responses adjusted to a confronted feature of social stimuli and situations, along with the expression of c-Fos as a marker of neuronal activity in selected brain areas involved in the regulation of social behavior. The function of the targeted brain area was confirmed by chemogenetic manipulation. We also examined the social peptides, oxytocin and vasopressin neurons of the major brain regions that are associated with the regulation of social behavior. Our data indicate that male BTBR mice are less responsive to the presentation of social stimuli and the expression of social signaling responses, which is paralleled by blunted c-Fos responsivity and vasopressin neurons morphological changes in selected brain areas, including the posterior bed nucleus of the stria terminalis (pBnST) and lateral habenula (LHb) in BTBR mice. Further investigation of LHb function revealed that chemogenetic inhibition and activation of LHb activity can induce a change in scent marking responses in both B6 and BTBR mice. Our elucidation of the downstream LHb circuits controlling scent marking behavior indicates intact function in BTBR mice. The altered morphological characteristics of oxytocin neurons in the paraventricular nucleus of the hypothalamus and vasopressin-positive neurons and axonal projections in the pBnST and LHb appear to underlie the dysfunction of scent marking responses in BTBR mice. (300/300 words).
Topics: Humans; Mice; Male; Animals; Autistic Disorder; Oxytocin; Habenula; Septal Nuclei; Mice, Inbred C57BL; Mice, Inbred Strains; Social Behavior; Disease Models, Animal
PubMed: 36543023
DOI: 10.1016/j.psyneuen.2022.106004